Mitochondrial Dysfunction May Play a Role in Autism Spectrum Disorders Etiology

Caroline Cassels

April 15, 2008

April 15, 2008 (updated April 25, 2008) (Chicago, Illinois) — New research suggests mitochondrial dysfunction may play a role in the etiology of autism spectrum disorders (ASD) in a subset of this patient population.

Here at the American Academy of Neurology 60th Annual Meeting, a retrospective analysis of 41 children with ASD who were being evaluated for suspected mitochondrial disease showed that 32 (78%) had defects in skeletal muscle oxidative phosphorylation (OXPHOS) enzyme function and 29 of 39 (74%) harbored abnormalities in the OXPHOS proteins.

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"We're very excited by these findings, and, based on these results, we will continue to pursue this [mitochondrial dysfunction] as a potential cause in a segment of the autistic population," principal investigator John Shoffner, MD, owner of Medical Neurogenetics, in Atlanta, Georgia, told Medscape Neurology & Neurosurgery.

While it is common for patients with mitochondrial disorders to have autistic features, Dr. Shoffner said his team investigated whether the opposite was true, that patients with ASD had indicators of underlying mitochondrial disease.

Study subjects were children aged 2 to 16 years who had a confirmed diagnosis of ASD and were referred for investigation of possible mitochondrial dysfunction due to the presence of markers for mitochondrial dysfunction, including increased lactate, pyruvate, and/or alanine.

Significant Numbers of Affected Individuals?

According to Dr. Shoffner, previous recent research has reported that up to 20% of children with autism have hyperlactacidemia and increased ratios of lactate/pyruvate.

"When you consider the frequency of autism in the general population, and you take 20% of that as a rough estimate of the proportion of children that may have these biomarkers [of mitochondrial dysfunction], it begins to raise some interesting questions about how to approach diagnosis, mechanism of disease, and patient management in what could turn out to be significant numbers of individuals," said Dr. Shoffner.

To find a possible explanation for elevated lactate levels, the investigators conducted a more detailed investigation that included analysis of mitochondrial enzyme activity in skeletal muscle biopsies.

They found defects in a series of selected representative proteins from each of the 5 enzyme complexes, which are responsible for producing and synthesizing energy in the muscles.

"Not only did we find enzyme defects in these patients, but we also took the investigation a step further and isolated and examined selected proteins involved in oxidative phosphorylation and found many of the proteins were also abnormal," said Dr. Shoffer.

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The researchers found defects in all 5 enzyme complexes, often described as the body's "power plants." Complex 1 abnormalities were the most common, with 41% of patients affected by OXPHOS enzyme and protein chemistry criteria. In addition to enzyme-function abnormalities, the investigators also found evidence of degradation of their proteins.

The muscle mitochondrial DNA (mtDNA) was sequenced in 40 of the patients. Of these, 75% (30/40) had normal mtDNA. Two subjects had heteroplasmic mtDNA mutations, which are often a marker for pathogenicity. The remainder had changes in the mtDNA that are still under investigation.

According to Dr. Shoffner, these data indicate that nuclear DNA mutations are the most likely causes of the mitochondrial defects. However, mtDNA mutations do occur.

"Obviously, autism is not a single condition but a true spectrum of disorders. There are many ways in which the genes can go awry, and our hope is that this study will open the door to a greater understanding of at least 1 subset of this patient population with metabolic and enzymologist changes," he said.

However, he added, further research in unselected populations of autistic patients is needed to confirm these findings.

Bruce H. Cohen, MD, a staff physician and pediatric neurologist at the Cleveland Clinic in Ohio, who specializes in ASD and mitochondrial disorders, said he is "enthusiastic" about the study's findings.

"Although these are newly presented data, those of us in the field of mitochondrial disease have been seeing these nonspecific electron-transport-chain enzymology changes in children with autism spectrum disorders for some time.

"But what is really interesting are the findings from analysis of the mitochondrial protein analysis, which showed evidence of mitochondrial dysfunction. Furthermore, the fact that 2 of these 40 patients had novel mitochondrial DNA was really fascinating," Dr. Cohen told Medscape Neurology & Neurosurgery.

However, Dr. Cohen noted at this point the clinical utility of these results is limited.

"For the physician out there who sees a child with ASD and neurologic regression, these findings may mean that child ought to be considered for further investigation with biochemical screening tests, mitochondrial DNA testing, and possibly even muscle biopsy if the clinical implications are appropriate," he said.

However, he added, since at this point there's no definitive treatment for mitochondrial disease, the immediate value of this research may lie in providing genetic screening and counseling to families who have a child with this profile.

The study is supported by Medical Neurogenetics, which conducted the testing. Dr. Shoffner is an owner of Medical Neurogenetics.

American Academy of Neurology 60th Annual Meeting: Abstract IN1-1.004. Presented April 13, 2008.


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